Several studies, including randomized clinical trials, have provided strong evidence for a beneficial effect of calcium and vitamin D on colorectal cancer and further suggest a positive interaction between these 2 nutrients. The overall goal of this proposal is to better understand whether polymorphisms in key genes of the calcium and vitamin D interrelated pathway - calcium sensing receptor (CASR) and vitamin D 1-alpha hydroxylase encoded by CYP27B1 -are associated with colorectal cancer risk. Although several experimental studies support that both CASR and CYP27B1 are promising candidate genes, very few studies have related variants in CASR to colorectal tumors. Results from a recent study that we conducted showed a significant association between 3 non-synonymous SNPs in CASR and colorectal adenomas, an established precursor of colorectal cancer. To follow up on these promising results, we propose to: 1) evaluate the association of genetic polymorphisms in CASR and CYP27B1 and risk of colon cancer; 2) examine the interaction between genetic polymorphisms in CASR, CYP27B1, and our existing data on polymorphisms in vitamin D receptor and the risk of colon cancer; and 3) determine whether genetic., polymorphisms in CASR or CYP27B1 modify previously observed inverse associations between supplemental and dietary intake of calcium and vitamin D and colon cancer risk. Data and specimens from a previously completed population-based case-control study of colon cancer (1676 cases, 2004 controls) will be used here to address the specific aims. We will identify polymorphisms by resequencing CASR and using existing sequence data for CYP27B1 and select tagging polymorphisms based on functionality, e.g. those likely to affect protein transcription or function, and an algorithm to capture the common genetic variation. We will conduct genotype and haplotype analysis. [unreadable] As data have been previously collected, this proposal is a cost-effective approach investigating the genetic variation in key genes of the calcium and vitamin D pathway, and will shed light on the mechanism underlying the protective effect of calcium and vitamin D against colon cancer. Genetic variation may be found to alter the risk of colon cancer or modify the chemopreventive response to calcium and vitamin D, which is of particular importance given the incidence of colorectal cancer and the very common use of calcium and vitamin D supplements in the United States. [unreadable] [unreadable] [unreadable]